DESCRIPTION (Investigator's abstract): The regulation of blood flow within the brain is characterized by extraordinary precision and speed. The high energy demands of active neurons and the restricted patterns of neuronal activity necessitate accurate temporal and spatial control over the cerebral microvasculature. This highly specIfic control suggests the existence of neurovascular mechanisms which couple blood flow and neuronal activity. The central goal of this proposal will be to; identify cellular substrates and mechanisms of local neurovascular communication. Studies of local neurovascular communication within the brain have historically been hampered by the complexity of the neuropil; parenchymal vessels are quite small and are deeply embedded in a meshwork of neural and glial elements. We present here a newly-developed model system that permits the simultaneous analysis of neuronal and microvascular elements in deep brain structures. This system will be utilized to examine several fundamental issues of local neurovascular signalling. The studies proposed herein will: I) characterize the effects of various forms of local neuronal activity on regional microvessels, II) identify the structural substrates for local neurovascular communication, and III) evaluate the role of neuronally-derived signal molecules as synaptic and/or paracrine messengers in local neurovascular communication. The manner in which cerebral microvessels respond to changes in local neuronal activity is, at best poorly understood. The present proposal will provide important insights into local neurovascular communication and the mechanisms underlying this form of intercellular signalling. The results of the proposed studies will have significant clinical as well as theoretical implications. In addition to enhancing our comprehension of a fundamental CNS function, the findings will contribute to a basic understanding of how microvessels might participate in cerebral pathology. Disturbances in microvascular function are thought to participate in the pathophysiology of ischemia and head injury. In order to optimize the restoration of blood flow under these conditions, it will be necessary to identify strategies for manipulatIng parenchymal vessels. The hopes for achieving this goal will ultimately depend on a clear understanding of how local neurovascular control is achieved. The current proposal will provide a critical foundation for this effort.